Bottom Line:
STLV-1 Tax and SBZ have functions similar to those of their counterparts in HTLV-1.This study demonstrates that Japanese macaques naturally infected with STLV-1 resemble HTLV-1 carriers and are a suitable model for the investigation of persistent HTLV-1 infection and asymptomatic HTLV-1 carrier state.Using these animals, we verified that mogamulizumab, which is currently used as a drug for relapsed ATL, is also effective in reducing the proviral load in asymptomatic individuals.

Background: Human T-cell leukemia virus type 1 (HTLV-1) causes chronic infection leading to development of adult T-cell leukemia (ATL) and inflammatory diseases. Non-human primates infected with simian T-cell leukemia virus type 1 (STLV-1) are considered to constitute a suitable animal model for HTLV-1 research. However, the function of the regulatory and accessory genes of STLV-1 has not been analyzed in detail. In this study, STLV-1 in naturally infected Japanese macaques was analyzed.

Conclusions: STLV-1 Tax and SBZ have functions similar to those of their counterparts in HTLV-1. This study demonstrates that Japanese macaques naturally infected with STLV-1 resemble HTLV-1 carriers and are a suitable model for the investigation of persistent HTLV-1 infection and asymptomatic HTLV-1 carrier state. Using these animals, we verified that mogamulizumab, which is currently used as a drug for relapsed ATL, is also effective in reducing the proviral load in asymptomatic individuals.

Figure 3: Comparison of the amino acid sequences of STLV-1 Tax and SBZ with those of HTLV-1 Tax and HBZ. Amino acid sequences of STLV-1 Tax (A) and SBZ (B) derived from an STLV-1+ Japanese macaque (Mf-5) are compared respectively with those of HTLV-1 Tax and HBZ from two isolates. Asterisk represents the termination codon. Accession number: [GenBank:J02029] (ATK) and [GenBank:L02534] (Mel5).

Mentions:
Analysis of the STLV-1 pX region suggests the presence of tax coding gene and an antisense transcript in the minus strand of STLV-1 similar to HBZ. In order to examine if STLV-1 tax and SBZ genes are transcribed and processed to be mature mRNAs in STLV-1-infected PBMCs, STLV-1 tax and SBZ transcripts were amplified by RT-PCR using the primers flanking the putative splicing site (Figure 2). The length of the amplified fragments was comparable to that of the corresponding HTLV-1 transcripts, which are approximately 240 bp for tax and 310 bp for HBZ. We further verified that STLV-1 tax and SBZ transcripts are spliced at exactly the same location as HTLV-1 tax and spliced form of HBZ[11,18], respectively (Figure 2). To investigate the molecular functions of STLV-1 Tax and SBZ, we cloned the coding sequences of those proteins from the STLV-1 provirus in a Japanese macaque (Mf-5). Approximately 91% of the coding sequence of tax was identical in HTLV-1 (ATK) and Japanese macaque STLV-1, and 82% in HBZ (ATK) and Japanese macaque SBZ. Phylogenetic analyses show that Japanese macaque STLV-1 env in this study is close to Melanesian subtype C [5] (Additional file 1). Therefore, the STLV-1 protein sequences were aligned with HTLV-1 prototype ATK (subtype A) as well as Mel5 (subtype C) for comparison, and presented in Figure 3. Approximately 93% of the STLV-1 Tax amino acid sequence was identical to that of HTLV-1 Tax (Figure 3A) and approximately 73% of the amino acid sequence of SBZ was identical to that of HBZ (Figure 3B). Notably, SBZ has some insertions and deletions, resulting in an excess of three amino acids compared with HBZ.

Figure 3: Comparison of the amino acid sequences of STLV-1 Tax and SBZ with those of HTLV-1 Tax and HBZ. Amino acid sequences of STLV-1 Tax (A) and SBZ (B) derived from an STLV-1+ Japanese macaque (Mf-5) are compared respectively with those of HTLV-1 Tax and HBZ from two isolates. Asterisk represents the termination codon. Accession number: [GenBank:J02029] (ATK) and [GenBank:L02534] (Mel5).

Mentions:
Analysis of the STLV-1 pX region suggests the presence of tax coding gene and an antisense transcript in the minus strand of STLV-1 similar to HBZ. In order to examine if STLV-1 tax and SBZ genes are transcribed and processed to be mature mRNAs in STLV-1-infected PBMCs, STLV-1 tax and SBZ transcripts were amplified by RT-PCR using the primers flanking the putative splicing site (Figure 2). The length of the amplified fragments was comparable to that of the corresponding HTLV-1 transcripts, which are approximately 240 bp for tax and 310 bp for HBZ. We further verified that STLV-1 tax and SBZ transcripts are spliced at exactly the same location as HTLV-1 tax and spliced form of HBZ[11,18], respectively (Figure 2). To investigate the molecular functions of STLV-1 Tax and SBZ, we cloned the coding sequences of those proteins from the STLV-1 provirus in a Japanese macaque (Mf-5). Approximately 91% of the coding sequence of tax was identical in HTLV-1 (ATK) and Japanese macaque STLV-1, and 82% in HBZ (ATK) and Japanese macaque SBZ. Phylogenetic analyses show that Japanese macaque STLV-1 env in this study is close to Melanesian subtype C [5] (Additional file 1). Therefore, the STLV-1 protein sequences were aligned with HTLV-1 prototype ATK (subtype A) as well as Mel5 (subtype C) for comparison, and presented in Figure 3. Approximately 93% of the STLV-1 Tax amino acid sequence was identical to that of HTLV-1 Tax (Figure 3A) and approximately 73% of the amino acid sequence of SBZ was identical to that of HBZ (Figure 3B). Notably, SBZ has some insertions and deletions, resulting in an excess of three amino acids compared with HBZ.

Bottom Line:
STLV-1 Tax and SBZ have functions similar to those of their counterparts in HTLV-1.This study demonstrates that Japanese macaques naturally infected with STLV-1 resemble HTLV-1 carriers and are a suitable model for the investigation of persistent HTLV-1 infection and asymptomatic HTLV-1 carrier state.Using these animals, we verified that mogamulizumab, which is currently used as a drug for relapsed ATL, is also effective in reducing the proviral load in asymptomatic individuals.

Background: Human T-cell leukemia virus type 1 (HTLV-1) causes chronic infection leading to development of adult T-cell leukemia (ATL) and inflammatory diseases. Non-human primates infected with simian T-cell leukemia virus type 1 (STLV-1) are considered to constitute a suitable animal model for HTLV-1 research. However, the function of the regulatory and accessory genes of STLV-1 has not been analyzed in detail. In this study, STLV-1 in naturally infected Japanese macaques was analyzed.

Conclusions: STLV-1 Tax and SBZ have functions similar to those of their counterparts in HTLV-1. This study demonstrates that Japanese macaques naturally infected with STLV-1 resemble HTLV-1 carriers and are a suitable model for the investigation of persistent HTLV-1 infection and asymptomatic HTLV-1 carrier state. Using these animals, we verified that mogamulizumab, which is currently used as a drug for relapsed ATL, is also effective in reducing the proviral load in asymptomatic individuals.